Introduction
The global obesity epidemic demands innovative strategies for weight management and obesity prevention. Given the significant contribution of obesity to comorbidities like diabetes and cardiovascular diseases, effective weight-reduction strategies are crucial. The gut microbiota, recognized as a key regulator of host physiology, presents a promising avenue for anti-obesity interventions through dietary modifications. This article delves into the potential of resistant starch (RS) as a functional food ingredient for obesity treatment, explores its impact on gut microbiota, and examines novel metabolic pathways that could revolutionize weight loss research.
Resistant Starch (RS) and Weight Loss
Resistant starch (RS) is a type of fermentable dietary fiber that resists digestion in the small intestine and undergoes fermentation by gut microbiota in the colon. Studies in rodents suggest that RS can decrease total body fat, particularly visceral fat.
Clinical Trial Results
A randomized, crossover clinical trial involving individuals with excess body weight investigated the effect of RS supplementation on obesity and metabolic phenotypes. Participants consumed either high-amylose maize (HAM-RS2) or control starch (CS) as part of an isoenergetic and balanced diet over two 8-week intervention periods, separated by a 4-week washout period.
The primary outcome, body weight, significantly decreased after the RS intervention, with a net absolute change of -2.81 kg compared to the CS intervention. Fat mass and waist circumference also reduced significantly after the RS intervention. Abdominal magnetic resonance imaging (MRI) revealed lower visceral fat areas (VFA) and subcutaneous fat areas (SFA) following RS consumption. Glucose tolerance and insulin sensitivity improved significantly after the RS intervention, as indicated by an increased glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Serum levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)α and interleukin (IL)-1β, were significantly lower after RS consumption. Daily excretion of faecal non-esterified fatty acid (NEFA), triglycerides (TGs), and total cholesterol (TC) were significantly higher following RS consumption, suggesting decreased lipid absorption. Circulating levels of angiopoietin-like 4 (ANGPTL4) were significantly increased, while serum fibroblast growth factor 21 (FGF21) significantly reduced after RS consumption.
Reshaping Gut Microbiota
Shotgun metagenomic sequencing revealed that the RS intervention altered the composition of the gut microbiome. Prevotella copri, Bacteroides stercoris, and Faecalibacterium prausnitzii were the most prevalent species across samples. Non-metric multidimensional scaling (NMDS) analysis showed a separation between RS and CS samples, indicating significant differences in gut microbiota composition.
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The Importance of Gut Microbiota
The gut microbiota has been increasingly recognized as an important regulator of host physiology and pathophysiology. Specifically, previous studies have reported that gut microbiota regulates inflammation, fat storage and glucose metabolism. The rational manipulation of the gut microbiome by dietary interventions might be a promising anti-obesity strategy.
Prebiotics, including polysaccharides, oligosaccharides and other fermentable dietary fibres, increase the amount of beneficial gut microbiota, notably certain Bifidobacterium and Lactobacillus spp. These bacteria diminish pathogen populations, fortify the gut barrier and mitigate the inflammatory response.
Insights from both human trials and mechanistic studies in gnotobiotic animals are crucial to establish the causality between microbiome alterations and host biological responses. Furthermore, these studies are vital to comprehend the mechanisms connecting microbiome changes to the physiological advantages of prebiotics or other fermentable dietary fibres.
Caveats and Future Directions
Human data showed that there was no impact on the total body weight of individuals with metabolic syndrome after being fed RS for a duration spanning 4 to 12 weeks. Low-fat diets supplemented with RS had beneficial effects on the hosts, but high-fat diets attenuated the RS fermentation and the beneficial effects. This may be one possible explanation as to why RS seemingly had no impact on body weight in the clinical trials described above, as those clinical trials did not have a high compliance rate to the diet.
RS’s potential as a functional, adaptable food ingredient for obesity treatment in humans and the modulation of metabolic benefits by RS-related gut microbiome alterations remain unclear. Thus, a robust trial in obese individuals is essential to substantiate claims about RS’s impact on diverse physiological aspects in consumers and the required dosage. Moreover, multi-omics approaches and gnotobiotic animal models should be used to systematically and mechanistically connect the influence of RS on the gut microbial community and the host’s metabolism.
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Novel Metabolic Pathways and Weight Loss
Recent research has uncovered novel metabolic pathways that offer promising new targets for obesity treatment.
BHB-Phe: A Body-Produced Appetite Regulator
Researchers have identified a novel compound called BHB-Phe, which is naturally produced by the body and regulates appetite and weight by activating neurons in the brain. BHB-Phe is produced when an enzyme called CNDP2 joins BHB to amino acids. BHB-Phe activates neural populations in the hypothalamus and brainstem, suppressing feeding and reducing body weight. Interestingly, the CNDP2 enzyme that produces BHB-Phe also produces a related compound called Lac-Phe, which is produced during exercise and can reduce food intake and obesity in mice.
BRP: A Semaglutide-Like Peptide
A naturally occurring molecule, BRP, identified by researchers, appears similar to semaglutide in suppressing appetite and reducing body weight. BRP is generated from a prohormone by prohormone convertase 1/3. BRP reduced food intake by up to 50% in both lean mice and minipigs. Obese mice treated with daily injections of BRP for 14 days lost an average of 3 grams, due almost entirely to fat loss.
Brown Fat Cells from Smooth Muscle
Researchers have uncovered a new source of energy expending brown fat cells, which points towards potential new therapeutic options for obesity. Specifically, smooth muscle cells expressing the Trpv1 receptor were identified as a novel source of energy-burning brown fat cells (adipocytes). The team employed modern single-cell RNA sequencing approaches to try to identify all types of cells present. Further investigations with mouse models confirmed that the Trpv1-positive smooth muscle cells gave rise to the brown energy-burning version of fat cells especially when exposed to cold temperatures.
Targeting Mitch to Boost Metabolism
Scientists found that disabling a single protein, Mitch, can boost metabolism and block fat formation, laying the groundwork for a new kind of obesity treatment. When they turned off the Mitch gene in mice, the mice didn’t just avoid gaining weight. Switching off Mitch in human cells also sped up the burning of fats and carbohydrates. The mice with the turned off Mitch gene led to improved performance in stress tests and heart function. When Mitch protein is deleted, the mitochondrial network collapses, the organelles separate, the efficiency of energy production declines - and the cell goes into a permanent state of energy deprivation.
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The Importance of Diet and Lifestyle
Strictly following a diet - either healthy low-carb or healthy low-fat - was what mattered for short-term weight loss during the first six months. The study showed that just cutting calories or exercising were not enough to sustain weight loss over a year. The predictive information gleaned from the gut microbiome, proteomic analysis and respiratory quotient signatures is laying the foundation for personalized diets. Low-carb diets should be based on monounsaturated fats and high in vitamins K, C and E.
Obesity and Inflammation
Obesity is a disease characterized by an inflammatory process in the adipose tissue due to diverse infiltrated immune cells, an increased secretion of proinflammatory molecules, and a decreased secretion of anti-inflammatory molecules. On the other hand, obesity increases the risk of several diseases, such as cardiovascular diseases, diabetes, and cancer. Their treatment is based on nutritional and pharmacological strategies. However, natural products are currently implemented as complementary and alternative medicine (CAM). Polyphenols and fiber are naturally compounds with potential action to reduce inflammation through several pathways and play an important role in the prevention and treatment of obesity, as well as in other non-communicable diseases.
Adipose tissue was previously considered as a static tissue (reservoir for energy). Studies have referred to adipose tissue as a dynamic tissue (metabolically active organ). The morphophysiological change of adipose tissue during obesity induces a chronic low-grade inflammatory state, also referred to as parainflammation (intermediate state between basal and inflammatory) or metainflammation (metabolically triggered inflammation).
When obesity occurs, an inflammatory process originates, which is known as a low-grade chronic inflammation response of prolonged time, and is the result of increasing fat tissue due to excess nutrient consumption. On the other hand, inflammation of adipose tissue is also described as a body’s natural or biological reaction against pathogens and harmful stimuli caused by toxic compounds, damaged cells, and metabolic factors. During this inflammatory process, there is excessive segregation of inflammatory factors known as adipokines, bioactive molecules responsible for the origin of inflammation and insulin resistance associated with obesity, segregated by adipocytes that include TNF-α, IL-6, IFN-γ, plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein-1 (MCP1), IL-1β, IL-8, IL-10, IL-15, leukemia inhibitory factor (LIF), hepatocyte growth factor (HGF), apolipoprotein amyloid A3 seric (SAA3), macrophage migration inhibitory factor (MIF), potent inflammatory modulators, such as leptin, adiponectin, resistin, and C-reactive protein (CRP), and these maintain both negative and positive effects, such as the maintenance of oxidative stress, changes in autophagy patterns, tissue necrosis, etc.
Obesity-Related Diseases
Type 2 Diabetes
Since the 1990s, observational studies in humans described that plasma biomarkers of inflammation (CRP and IL.6) are higher in type-2 diabetic patients. Studies in vitro showed that TNF-α could impair insulin signaling in 3T3-L1 adipocytes, leading to the reduced expression of insulin receptor substrate-1 (IRS-1) and Glut4. Chronic obesity progression also induces an inflammatory process in the pancreas caused by the increased flux of no esterified or free fatty acids (FFA) and the subsequent penetration of macrophages to increase cytokine infiltration, including TNF-a, IL-6, and MCP-1, leading to β-cell dysfunction.
Cardiovascular Disease
Cardiovascular disease (CVD) is one of the first causes of mortality in several countries. In people with obesity, there is an activation of the systemic inflammation unchained from the accumulation of macrophages in adipose tissue that at the same time stimulate the secretion of pro-inflammatory proteins, mainly TNF-α, IL-6 and C-reactive protein (CRP), leptin, adipocyte fatty acid-binding protein, and several novel adipokines, such as chemerin resistin, visfatin, and vaspin.
Cancer
According to different authors, inflammation linked to obesity is considered a risk factor that improves the initiation and progression of various types of cancer. In addition, the presence of macrophages in obesity causes the infiltration of tumors, and increases the inflammatory tumor microenvironment caused by cytokines, prostaglandins, and angiogenic factors.
Non-Alcoholic Fatty Liver Disease (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) is a very complex disorder and is the most common liver disorder related to T2D. It has been shown that, during NAFLD, hepatic stellate cells (HSCs) and Kupffer cells increase the secretion of TNF-α and promote the recruitment of immune cells, perpetuating the inflammatory process.